Pharmaceutical paste formulations for site specific application

ABSTRACT

A pharmaceutical paste formulation containing an active ingredient, an API solubilizer, a cross-linking agent, a consistency improver, a rheology modifier, a humectant, and a liquid base.

RELATED APPLICATIONS

The present application is a continuation of U.S. patent applicationSer. No. 17/002,183 filed Aug. 25, 2020, entitled Pharmaceutical PasteFormulations for Site Specific Application, which claims the benefit ofU.S. Provisional Patent Application Ser. No. 62/893,952, filed Aug. 30,2019, entitled Pharmaceutical Paste Formulations for Site SpecificApplication, each of which is hereby incorporated in its entirety byreference herein.

BACKGROUND 1. Field

The present invention relates to improved pharmaceutical gelformulations having enhanced spreadability and that can be applied usinga wide range of devices for site specific application (e.g.,single-and-multi-use squeezable tubes, syringes, etc.).

2. Discussion of Prior Art

Recurrent aphthous stomatitis (commonly referred to as canker sores,hereinafter referred to as “RAS”) is a common oral disorder affectingover half of the population of the United States where painful circularyellowish sores develop on the oral mucosa. RAS typically affects thesofter parts of the mouth that move, such as the tongue, soft palate,cheeks, and lips. RAS is said to be “recurrent” because a sore usuallyreappears in the same or a new location after healing. In some cases,multiple ulcers are present, some of which may be healing while othersare just starting to appear. There are three main subtypes of RAS: (1)minor aphthous stomatitis; (2) major aphthous stomatitis; and (3)herpetiform aphthous stomatitis. Minor aphthous stomatitis is the mostcommon subtype, constituting more than 80% of RAS cases, and isgenerally characterized by small (i.e., less than 1 cm in diameter)sores that heal in approximately 1-week and do not typically result inthe formation of scar tissue. Major aphthous stomatitis is the secondmost common form of RAS, constituting approximately 15% of RAS cases,and is generally characterized by slightly larger (i.e., greater than 1cm in diameter) sores that take longer to heal (i.e., two or more weeks)and are extremely painful and often result in the formation of scartissue. Herpetiform aphthous stomatitis is the least common subtype ofRAS, occurring in less than 5% of RAS cases, and is generallycharacterized by clusters of very small ulcers (i.e., less than 1 mm)that typically heal in approximately 1-week.

The treatment of RAS with sucralfate is generally known. For instance,ProThelial™ “is polymerized sucralfate malate paste that forms aprotective layer over the oral mucosa by adhering to the mucosalsurface” marketed by Mueller Medical International LLC. ProThelial™ is athick gel packaged in a wide mouth bottle. ProThelial™ users areinstructed to remove the product from the bottle using a spoon and toapply the product to the affected area using the “tongue to apply pastethroughout the mouth (as if using tongue to remove peanut butter fromteeth).” Known sucralfate formulations for treating RAS require broadrange application to the entire mouth by swishing/gargling and tend todry-up quickly in storage due to high solid content and sucralfate'shigh water absorbing capacity.

Thus, there is a need for sucralfate formulations that can be applied toulcers on a site specific basis using an applicator, such as asqueezable tube, and that will not dry and harden in storage.

The foregoing background discussion is intended to provide informationrelated to the present invention which is not necessarily prior art.

SUMMARY OF THE INVENTION

Pharmaceutical gel formulations according to the present inventionprovide several advantages over the prior art. For instance, certainembodiments relate to soothing mucoadhesive pharmaceutical gels fortreating RAS that: can be provided to patients in site specificapplicators (such as a squeezable tube), which enable direct applicationon the lesions; spread easily and adhere better (relative to the priorart) to the affected area; will not exhibit increased viscosity over alonger shelf-life due to moisture loss and/or reactions betweenexcipients; provide reduced irritability and improved taste; do notrequire the patient or physician to perform additional processing stepsprior to application; and/or are free of preservatives. It should beunderstood that the present invention is not limited to the foregoingadvantages and that other technical advantages may become readilyapparent to one of ordinary skill in the art after review of thedescription.

Pharmaceutical gel formulations according to certain aspects of thepresent invention have Bingham plastic rheology, which means theinventive formulations behave as viscoplastic (i.e., behaves as a rigidbody at low stresses but flows as a viscous fluid at high stress). Thisrheological property enables users to accurately deliver thepharmaceutical gel directly on the ulcerative lesions using a sitespecific applicator (such as a squeezable tube having an applicatortip). Such pharmaceutical gel formulations can be described as acongealed base having a high proportion of solids in a finely dispersedform.

Pharmaceutical gel formulations according to the present inventionretain moisture; for instance, by inclusion of one or more humectantsand/or rheology modifiers. Moisture retention facilitates fluidity by,among other things, reducing resistance to movement of solid particlesin the dispersed phase. Known sucralfate products do not retain adequatemoisture, and solids in the dispersed phase tend to aggregate, whichcontributes to their higher viscosity and limited application.

Certain aspects of the present invention relate to a medical deviceconsisting of a ready-to-use topical pharmaceutical formulationcontained within functional packaging designed to enable the user toapply the formulation directly on the treatment location.

The foregoing summary is provided to introduce a selection of conceptsin a simplified form that are further described below in the detaileddescription. This summary is not intended to identify key features oressential features of the claimed subject matter, nor is it intended tobe used to limit the scope of the claimed subject matter. Other aspectsand advantages of the present invention will be apparent from thefollowing detailed description, working examples, and the accompanyingdrawing figures.

BRIEF DESCRIPTION OF THE DRAWING FIGURES

Certain aspects of certain embodiments of the invention are described indetail below with reference to the attached figures, wherein:

FIG. 1 is a side perspective view of a medical device configured tocontain a pharmaceutical gel formulation manufactured in accordance withcertain embodiments of the present invention; and

FIG. 2 is an enlarged, partially sectioned cross-sectional view of themedical device of FIG. 1 .

The figures do not limit the present invention to the specificembodiments disclosed and described herein. The emphasis instead beingplaced upon clearly illustrating certain principles of a preferredembodiment.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

In addition to the other terms expressly defined herein, for thepurposes of this disclosure and claims, the following terms, units,symbols, words, abbreviations, acronyms, phrases, and/or other thingsshall have the respective meanings assigned to them as follows (andcognate expressions shall bear corresponding meanings): the symbol “%”means percent; the unit symbol “% w/w” means percent-by-weight, theamount/concentration of one or more components in a group of components,which can be calculated by dividing the numerical value for the mass ofone or more components in a group of components by the numerical valuefor the mass of all of the components in the group and multiplying thequotient by 100; the unit symbol “° C.” means degree(s) in Celsius, aunit of temperature on the Celsius scale; the unit symbol “cfu” meanscolony-forming unit, the number of viable microorganisms in a sample;the unit symbol “cfu/g” means colony-forming units per gram, the numberof viable microorganisms per gram of a sample; the unit symbol “cm”means centimeter, a unit of length equal to one hundredth of a meter;the acronym “EAA” means ethylene acrylic acid copolymers; the acronym“EDTA” means the compound sodium ethylenediaminetetraacetic acid; theunit symbol “g” means gram(s), a unit of mass equal to 0.001 kg; theunit symbol “mm” means millimeter, a unit of length equal to onethousandth of a meter; the acronym “NMT” means not more than; the symbol“pH” refers to a measure of the hydrogen ion concentration in solutionand is also referred to as the degree of acidity or alkalinity; thephrases “pharmaceutical gel”, “sucralfate gel”, and “paste/gel” refer tothe dosage form (i.e., the physical form in which a drug is produced anddispensed) gel and/or paste as defined by the U.S. Food and DrugAdministration; the unit symbol “RH” means relative humidity; theacronym “rpm” means rotations per minute; and the unit symbol “μ” meansmicron, which is equal to 0.001 mm.

Certain aspects of the present invention are directed to pharmaceuticalgel formulations. In certain embodiments, pharmaceutical gelformulations preferably include one or more: active pharmaceuticalingredients; crosslinking agents; rheology modifiers; liquid bases;taste modifiers; and other excipients. However, those having ordinaryskill in the art will understand that other formulations are within thescope of the present invention.

In certain embodiments, the active pharmaceutical ingredient issucralfate. Sucralfate is a disaccharide polysulfate-aluminum compound,more specifically referred to as alpha-D-glucopyranoside,beta-D-fructofuranosyl, catkins (hydrogen sulfate), aluminum complexhaving the structure shown below:

Sucralfate has been used to manage lesions in the oral cavity (e.g.,aphthous ulcers, stomatitis, etc.). Sucralfate adheres to the mucosalsurface and forms a protective layer over the oral mucosa to reduceirritation and pain caused by lesions in the oral cavity. Sucralfate isan oral “anti-ulcer” and gastrointestinal drug, which has been used totreat or prevent the recurrence of ulcers by protecting stomach orduodenal lining from the effects of various irritants (e.g., alcohol,acetylsalicylic acid, hydrochloric acid, sodium hydroxide, sodiumtaurocholate, etc.). Sucralfate has also been considered as a first-linedrug therapy in the management of heartburn during pregnancy. Sucralfateis used as a topical drug for the healing of several types of epithelialwounds such as ulcers, inflammatory dermatitis, mucositis, and burnwounds.

In certain embodiments of the present invention, the pharmaceutical gelformulation includes sucralfate at a concentration ranging from about 3%w/w to about 15% w/w. In certain preferred embodiments, thepharmaceutical gel formulation includes sucralfate at a concentration ofabout 10% w/w.

In certain embodiments, the pharmaceutical gel formulation includes oneor more API solubilizers. For instance, sucralfate is practicallyinsoluble in water, so an API solubilizer may be incorporated in theformulation to decrease the pH of water and to solubilize sucralfate,which facilitates the polymerization of sucralfate. A wide range of APIsolubilizers can be used in the pharmaceutical gel formulations of thepresent invention, including, but not limited to, one or more APIsolubilizers selected from the group consisting of citric acid, lacticacid, malic acid, and tartaric acid. It should be understood thatcertain embodiments are not limited to the use of the foregoing APIsolubilizers. Furthermore, other ingredients may be used that functionas API solubilizers without departing from the spirit of the presentinvention.

In certain embodiments, the pharmaceutical gel formulation includes oneor more API solubilizers at a concentration ranging, preferably, fromabout 0.001% w/w to about 15% w/w. More preferably, the pharmaceuticalgel formulation includes one or more API solubilizers at a concentrationranging from about 0.05% w/w to about 10% w/w.

In certain embodiments, preferred API solubilizers improve thesolubility of the active ingredient in water. In certain embodiments,malic acid is used to improve the solubility of sucralfate in water,with the compositional ratio of malic acid to sucralfate in at least onepreferred embodiment being approximately one-to-two (1:2). In certainembodiments, malic acid also helps facilitate water retention in thepharmaceutical gel throughout its shelf life. It should be understoodthat certain embodiments of the present invention are not limited to theuse of malic acid as an API solubilizer. Furthermore, other ingredientsmay be used without departing from the spirit of the present invention.

In certain embodiments, the pharmaceutical gel formulation includes oneor more rheology modifiers. Rheology modifiers facilitate manufacture ofa pharmaceutical gel that is soft, spreadable, and will stay hydratedfor longer periods of time, which enables packaging of the inventivepharmaceutical gels in site specific applicators. A wide range ofrheology modifiers can be used in the pharmaceutical gel formulations ofthe present invention, including, but not limited to, one or morerheology modifiers selected from the group consisting of: carboxymethylcellulose; cellulose derivatives; ethyl cellulose; hydroxypropylcellulose; hydroxypropyl methylcellulose; methylcellulose;microcrystalline cellulose; natural polysaccharides such as chitosan,pectin, guar gum, etc.; polyvinyl alcohol; povidone; propyl cellulose;sodium carboxymethyl cellulose; and xanthan gum. It should be understoodthat certain embodiments are not limited to the use of the foregoingrheology modifiers. Furthermore, other ingredients that function asrheology modifiers may be used without departing from the spirit of thepresent invention.

In certain embodiments, the pharmaceutical gel formulation includes oneor more rheology modifiers at a concentration ranging, preferably, fromabout 0.05% w/w to about 30% w/w. More preferably, the pharmaceuticalgel formulation includes one or more rheology modifiers at aconcentration ranging from about 1% w/w to about 25% w/w.

Preferred rheology modifiers according to certain embodiments arenontoxic and compatible with other pharmaceutical ingredients.Furthermore, preferred rheology modifiers enable certain preferredcharacteristic properties of pharmaceutical gel formulations of thepresent invention; more particularly, preferred rheology modifiers:provide consistency to the formulation; provide increased viscosity inlow concentrations; exhibit good stability and viscosity properties overa wide range of pH levels and temperatures; maintain the preferredtexture properties of the formulation; and maintain the thickness andstability of the pharmaceutical gel during long-term storage at elevatedtemperatures. One such preferred rheology modifier according to certainembodiments is xanthan gum. Xanthan gum is a hydrophilic polymer.Xanthan gum is nontoxic and is compatible with a wide range ofpharmaceutical ingredients. Xanthan gum shows high viscosity at lowconcentrations, provides consistency to the pharmaceutical gelformulation, and helps maintain preferred textural properties of theinventive paste/gel formulations. Aqueous solutions of xanthan gum arestable over a wide range of pH levels (i.e., pH levels ranging fromabout three (3) to about twelve (12)). Xanthan gum remains stable inboth acidic as well as in alkaline conditions due to its rigid structureand resistance to changes in pH. Xanthan gum gels show pseudo plasticbehavior, the shear thinning is directly proportional to the shear rate;viscosity turns to normal immediately on release of shear stress. Itshould be understood that certain embodiments are not limited to the useof xanthan gum as a rheology modifier. Furthermore, other ingredientsmay be used as rheology modifiers without departing from the spirit ofthe present invention.

In certain embodiments, pharmaceutical gel formulations include one ormore humectants. A wide range of humectants can be used in thepharmaceutical gel formulations of the present invention, including, butnot limited to, one or more humectants selected from the groupconsisting of propylene glycol, polyethylene glycol, glycerin, sorbitol,hexylene glycol, and butylene glycol. It should be understood thatcertain embodiments are not limited to the use of a specific humectant.Furthermore, other ingredients that function as humectants may be usedwithout departing from the spirit of the present invention.

Preferred humectants according to certain embodiments facilitate waterretention in the inventive pharmaceutical gels, which enables suchpharmaceutical gels to be packaged in site specific applicators bypreventing drying and hardening of the pharmaceutical gel within suchapplicators. One such preferred humectant according to certainembodiments is propylene glycol. Propylene glycol facilitates waterretention in the pharmaceutical gel formulation over a sufficient periodof time, which enables such pharmaceutical gels to be packaged in sitespecific applicators. Furthermore, propylene glycol hydrates the mucosaand may help reduce irritation associated with lesions in the oralcavity, and can also improve palatability given its sweet taste. Itshould be understood that certain embodiments are not limited to the useof propylene glycol as a humectant. Furthermore, other ingredients maybe used without departing from the spirit of the present invention.

In certain embodiments, the pharmaceutical gel formulation includes oneor more humectants at a concentration ranging, preferably, from about0.05% w/w to about 30% w/w. More preferably, the pharmaceutical gelformulation includes one or more humectants at a concentration rangingfrom about 1% w/w to about 25% w/w.

In certain embodiments, one or more crosslinking agents are used tofacilitate polymerization of the active ingredient in the presence oforganic acids, acting as a cross-linker for the active ingredient andthe acid. A wide range of crosslinking agents can be used in thepharmaceutical gel formulations of the present invention, including, butnot limited to, one or more crosslinking agents selected from the groupconsisting of bicarbonates, calcium carbonate, magnesium carbonate, andmagnesium oxide. It should be understood that certain embodiments of thepresent invention are not limited to the use of a specific crosslinkingagent. Furthermore, other ingredients that function as crosslinkingagents may be used without departing from the spirit of the presentinvention.

In certain embodiments, the pharmaceutical gel formulation includes oneor more crosslinking agents at a concentration ranging, preferably, fromabout 0.001% w/w to about 10% w/w. More preferably, the pharmaceuticalgel formulation includes one or more crosslinking agents at aconcentration ranging from about 0.05% w/w to about 5% w/w.

In certain embodiments, the pharmaceutical gel formulations have a pHvalue of approximately 5 to about 7. At pH levels of less than about 4,sucralfate undergoes extensive polymerization and becomes a sticky,viscid gel. At pH levels of greater than about 4, a cross-linking agentfacilitates the desired characteristics of spreadability, adhesion, andmucosal affinity. In certain embodiments, calcium carbonate is apreferred cross-linking agent based on the chelation formation betweenthe calcium ions (Ca2+) of calcium carbonate and the aluminum ions(A13+) of the sucralfate complex. In certain embodiments, calciumcarbonate also acts as a buffering agent; maintaining the pH level ofsucralfate paste/gel at a range of about 5 to about 7, which isapproximately the same as the pH of saliva. In certain embodiments,calcium carbonate is used as a crosslinking agent at a concentrationranging, preferably, from about 1% w/w to about 5% w/w. It should beunderstood that certain embodiments are not limited to the use ofcalcium carbonate as a crosslinking agent. Furthermore, otheringredients may be used without departing from the spirit of the presentinvention.

In certain embodiments, where the pharmaceutical gel formulationincludes sucralfate and malic acid (as an API solubilizer), it may bepreferable to include malic acid and calcium carbonate in a specificratio of one-to-two (1:2) to avoid phase separation during theprocessing stage, which can cause sucralfate to precipitate-out of thefinal composition. It should be understood that certain embodiments arenot limited to the use of calcium carbonate as a crosslinking agentand/or malic acid as an API solubilizer. Furthermore, other ingredientsmay be used without departing from the spirit of the present invention.

In certain embodiments, the pharmaceutical gel formulation includes oneor more consistency improvers. Consistency improvers reduce lumping ofthe pharmaceutical gel formulation and improve the paste/gel's overallconsistency. In certain embodiments, calcium sulphate dihydrate is usedas a consistency improver to reduce lumping of sucralfate and calciumcarbonate and improve the pharmaceutical gel's consistency. It should beunderstood that certain embodiments of the present invention are notlimited to the use of a consistency improver. Furthermore, otheringredients that function as consistency improvers may be used withoutdeparting from the spirit of the present invention.

In certain embodiments, the pharmaceutical gel formulation includes oneor more consistency improvers at a concentration ranging, preferably,from about 0.001% w/w to about 10% w/w. More preferably, thepharmaceutical gel formulation includes one or more consistencyimprovers at a concentration ranging from about 0.01% w/w to about 1%w/w.

In certain embodiments, the pharmaceutical gel formulation includes oneor more stabilizers. Stabilizers are used to help the activepharmaceutical ingredient maintain desirable properties of thepharmaceutical product until it is used by the patient; for example,stabilizers can be used to control degradation of the active ingredient.Suitable stabilizers include, but are not limited to, organic acids andinorganic acids. In certain embodiments, preferred stabilizers includeethylenediaminetetraacetic acid (hereinafter referred to as “EDTA”)and/or sodium edetate; however, it should be understood that certainembodiments are not limited to the use of a stabilizer. Furthermore,other ingredients that function as stabilizers may be used withoutdeparting from the spirit of the present invention.

In certain embodiments, the pharmaceutical gel formulation includes oneor more liquid bases, which act as a vehicle for other ingredients. Incertain embodiments, the liquid base will, preferably, serve as both avehicle and a hydrating agent. In certain embodiments, thepolymerization of sucralfate with malic acid and calcium carbonate takesplace in the presence of purified water (as the liquid base). It shouldbe understood that certain embodiments are not limited to the use of aspecific liquid base. Furthermore, other ingredients that function as avehicle may be used without departing from the spirit of the presentinvention.

In certain embodiments, the pharmaceutical gel formulation includes aliquid base at a concentration ranging, preferably, from about 1% w/w toabout 95% w/w. More preferably, the pharmaceutical gel formulationincludes a liquid base at a concentration ranging from about 10% w/w toabout 90% w/w.

In certain embodiments, the pharmaceutical gel formulation includes oneor more taste modifiers that function to improve the palatability of theformulation. Taste modifiers may include one or more sweetening agents,flavor enhancers, and/or flavoring agents. In certain preferredembodiments of the present invention, the pharmaceutical gel formulationincludes one or more taste modifiers selected from the group consistingof stevia, aspartame, sucralose, neotame, acesulfame potassium,saccharin, and advantame; however, it should be understood that thepresent invention is not limited to the use of the foregoing tastemodifiers. Furthermore, other ingredients that function as tastemodifiers may be used without departing from the spirit of the presentinvention.

In certain embodiments, the pharmaceutical gel formulation includes oneor more taste modifiers at a concentration ranging, preferably, fromabout 0.005% w/w to about 10% w/w. More preferably, the pharmaceuticalgel formulation includes one or more taste modifiers at a concentrationranging from about 0.01% w/w to about 5% w/w.

Pharmaceutical gels manufactured in accordance with preferredembodiments of the present invention are capable of being packaged in asqueezable tube having a site specific applicator nozzle. For instance,pharmaceutical gels manufactured in accordance with preferredembodiments of the present invention are capable of being packaged in aprimary packaging tube similar to that described in Table 1 below andshown in FIGS. 1 and 2 .

TABLE 1 Parameter Description Package Type Laminated tube Length withshoulder (mm) 100 Length without shoulder (mm) 83.5 Tube diameter (mm)16 Inner Nozzle Diameter (mm) 0.61 Outer Nozzle Diameter (mm) 3.51Nozzle length (mm) 14.25 Tube wall thickness (mm) 0.18 Total Thickness(μ) 175 ± 10% Total GSM 186.96 ± 10% Shelf Life 2 years in tube form orwithout filled product Barrier layer Aluminum Foil Thickness 9 μ TIElayer EAA Thickness 20.5 μ Outer white film Polyethylene Thickness 75 μJoint type Butt joints (no overlapping) with heat resistant adhesivetapes on both sides. Manufacturer Essel Propack Ltd.

Similar primary packaging may be used without departing from the spiritof the present invention. For instance, a wide range of squeezablereservoirs configured to contain the pharmaceutical gel formulation arewithin the ambit of the present invention, including pouches, bags,balls, cylinders, and others. In certain preferred embodiments, withreference to the drawing figures, the medical device 1 includes asqueezable reservoir 3 configured to contain the pharmaceutical gelformulation (not shown) and a site specific applicator 5 projecting fromthe reservoir 3. The reservoir 3 includes a wall 7, which facilitatescontainment of the formulation. In certain embodiments, it may bepreferable for a shoulder 9 to be formed in wall 7 to facilitate flow toapplicator 5 when reservoir 3 is squeezed by the user. The site specificapplicator 5 includes a wall 11 defining an inner margin 13 that extendsfrom the proximal end 15 of applicator 5 to the outlet/opening 17 at thedistal end 19 of applicator 5. Margin 13 is arranged in fluidcommunication with reservoir 3 so that when the user squeezes reservoir3, the pharmaceutical gel formulation is expelled from reservoir 3,through margin 13, and out opening 17. Margin 13 has a width 21 in therange of about 0.5 mm to about 2 mm. In certain embodiments, the width21 of margin 13 is substantially the same between end 15 and end 17. Inother embodiments, it may be preferable for the width 21 of margin 13 todecrease from end 15 to end 17. In certain preferred embodiments, device1 includes a closure (not shown), such as a cap, to prevent dryingand/or contamination of the pharmaceutical gel formulation.

Additional advantages of the various embodiments will be apparent tothose skilled in the art upon review of the disclosure herein and theworking examples below.

EXAMPLES

The following working examples set forth preferred embodiments inaccordance with the present invention. It is to be understood, however,that these examples are provided by way of illustration and nothingtherein should be taken as a limitation upon the overall scope of theinvention.

Ingredients corresponding to Example 1 (10% sucralfate pharmaceuticalgel) are tabulated in Table 2, with the amount of each ingredient givenin respective percent weight-by-weight (% w/w). In Example 1, the activeingredient is sucralfate. In Example 1, the active strength ofsucralfate is about 10%.

TABLE 2 Ingredient Type % w/w Sucralfate Active Ingredient 10.000 Malicacid API Solubilizer 5.000 Calcium carbonate Crosslinking Agent 1.000Polyvinylpyrrolidone K-30 Rheology Modifier 3.820 PolyvinylpyrrolidoneK-90 Rheology Modifier 3.820 Calcium sulfate dihydrate ConsistencyImprover 0.100 EDTA Stabilizer 0.020 Sucralose Taste Modifier 0.020Propylene glycol Humectant 7.000 Purified water Liquid Base 69.220 TOTAL100.00

Procedure—Example 1

Step 1: triturate the batch quantity of malic acid to a fine powder byusing a mortar pestle.

Step 2: add the batch quantities of calcium carbonate and sucralfate,simultaneously, to the triturated malic acid of Step 1 under continuoustrituration until a uniform mixture is formed.

Step 3: add approximately 12% of the batch quantity of purified water tothe mixture of Step 2 under continuous trituration, mix well until athick, sticky gel is formed, and allow the mixture to soak forapproximately 30-minutes.

Step 4: add approximately 40% of the batch quantity of purified water toa container, and add the batch quantities of polyvinylpyrrolidone K-30and polyvinylpyrrolidone K-90 to the purified water under continuousstirring at about 800-rpm for approximately 10-minutes.

Step 5: add the batch quantities of EDTA, calcium sulfate dihydrate, andsucralose to the mixture of Step 4 under continuous stirring at about800-rpm for approximately 15-minutes.

Step 6: add and mix the paste of Step 3 to the mixture of Step 5 undercontinuous high speed stirring at about 1500-rpm for approximately120-minutes to form a uniform mixture.

Step 7: add and mix the batch quantity of propylene glycol to themixture of Step 6 under continuous high speed stirring at about1500-rpm.

Step 8: add the remaining batch quantity of purified water to themixture of Step 7 and stir continuously.

Step 9: let the mixture of Step 8 set for approximately 12-hours — apaste/gel should begin to form after approximately 5 to 6 hours.

Table 3: Characterization of the pharmaceutical gel formed in accordancewith Example 1.

TABLE 3 Appearance Opaque Texture Smooth Color White Assay (percentage)93.4

Ingredients corresponding to Example 2 (10% sucralfate pharmaceuticalgel) are tabulated in Table 4, with the amount of each ingredient givenin respective percent weight-by-weight (% w/w). In Example 2, the activeingredient is sucralfate. In Example 2, the active strength ofsucralfate is about 10%.

TABLE 4 Ingredient Type % w/w Sucralfate Active Ingredient 10.000 Malicacid API Solubilizer 5.000 Calcium carbonate Cross Linking Agent 2.500Xanthan gum Rheology Modifier 0.500 Calcium sulfate dihydrateConsistency Improver 0.100 Sucralose Taste Modifier 0.020 Propyleneglycol Humectant 7.000 Purified water Liquid Base 74.880 TOTAL 100.00

Procedure—Example 2

Step 1: add approximately 65% of the batch quantity of purified water toa vessel and add and dissolve the batch quantity of malic acid undercontinuous stirring at about 1200-rpm for approximately 10-minutes.

Step 2: add the batch quantity of sucralfate to the mixture of Step 1under continuous stirring at about 1800-rpm for approximately 30-minutes(a uniform dispersion should be observed).

Step 3: add the batch quantity of calcium carbonate to the mixture ofStep 2 under continuous stirring until a uniform mixture is formed(approximately 40-minutes).

Step 4: add the batch quantities of calcium sulfate dihydrate andsucralose to the mixture of Step 3 under continuous homogenization atabout 2500-rpm, until a uniform dispersion is formed.

Step 5: slowly add and dissolve the batch quantity of xanthan gum to thedispersion of Step 4 under continuous homogenization at about 2500-rpm.

Step 6: add and mix the batch quantity of propylene glycol to themixture of Step 5 under continuous stirring at about 1500-rpm forapproximately 10-minutes.

Table 5: Characterization of the pharmaceutical gel formed in accordancewith Example 2.

TABLE 5 Sample Appearance Texture Color EX 2 Opaque Smooth White EX 2¹Opaque Smooth White EX 2² Opaque Smooth White EX 2³ Opaque Smooth White¹one-month stability at 40° C. and 75% relative humidity (“RH”).²three-month stability 40° C. and 75% RH. ³three-month stability 25° C.and 60% RH.

Table 6: pH value and water content of the pharmaceutical gel formed inaccordance with Example 2.

TABLE 6 Water Content Sample pH (percentage) EX 2 6.38 69.1908 EX 2¹5.65 59.6283 EX 2² 5.86 60.7621 EX 2³ 5.75 62.0086 ¹one-month stabilityat 40° C. and 75% RH. ²three-month stability 40° C. and 75% RH.³three-month stability 25° C. and 60% RH.

Analysis results concerning the chemical characterization and acidneutralizing capacity (performed as given in United States Pharmacopeia(USP) general chapter <301>Acid-neutralizing capacity) of thepharmaceutical gel formed in accordance with Example 2 are tabulated inTable 7.

TABLE 7 Assay Sample (percentage) Acid Neutralizing Capacity EX 2 106.213.51 EX 2¹ 100.3 13.21 EX 2² 99.2 13.03 EX 2³ 104.1 13.2 ¹one-monthstability at 40° C. and 75% RH. ²three-month stability 40° C. and 75%RH. ³three-month stability 25° C. and 60% RH.

The results of a microbial enumeration analysis (conducted in accordancewith USP general chapter <61>microbiological examination of nonsterileproducts: microbial enumeration tests) of the pharmaceutical gel formedin accordance with Example 2 are tabulated in Table 8.

TABLE 8 Test Result Specification Total aerobic microbial count <10cfu/g NMT 10² cfu/g Total combined yeast and mold count <10 cfu/g NMT10¹ cfu/g Escherichia coli Absent/g Absent/g Pseudomonas aeruginosaAbsent/g Absent/g Staphylococcus aureus Absent/g Absent/g Salmonellaspecies Absent/10 g Absent/10 g

Modifications, additions, and/or omissions may be made to thecompositions, methods, and steps described herein without departing fromthe scope of the disclosure. For example, the ingredients of thecomposition and method for manufacture may be integrated or separated.Moreover, the method for manufacture disclosed herein may be prepared bymore, fewer, or other ingredients and the methods described may includemore, fewer, or other steps. Additionally, steps may be performed in anysuitable order.

Additional Considerations

As used herein, the term “specification” refers to all parts of thewritten description, including the working examples, and the claims ofthe present patent application.

As used in this specification, the phrase “and/or,” when used in a listof two or more items, means that any one of the listed items can beemployed by itself or any combination of two or more of the listed itemscan be employed. For example, if a composition is described ascontaining or excluding components A, B, and/or C, the composition cancontain or exclude A alone; B alone; C alone; A and B in combination; Aand C in combination; B and C in combination; or A, B, and C incombination.

As used in this specification, the terms “comprises,” “comprising,”“includes,” “including,” “has,” “having” or any other variation thereof,are intended to cover a non-exclusive inclusion. For example, a process,method, article, or apparatus that comprises a list of elements is notnecessarily limited to only those elements but may include otherelements not expressly listed or inherent to such process, method,article, or apparatus.

Approximating language, as used in this specification, may be applied tomodify any quantitative representation that could permissibly varywithout resulting in a change in the basic function to which it isrelated. Accordingly, a value modified by a term or terms, such as“about,” “approximately,” and “substantially” are not to be limited tothe precise value specified. In at least some instances, theapproximating language may correspond to the precision of an instrumentfor measuring the value. In this specification, range limitations may becombined and/or interchanged. Such ranges are identified and include allthe sub-ranges contained therein unless the context or languageindicates otherwise.

With respect to the use of substantially any plural and/or singularterms used in this specification, those having skill in the art cantranslate from the plural to the singular and/or from the singular tothe plural as is appropriate to the context and/or application. Thevarious singular/plural permutations may be expressly set forth hereinfor the sake of clarity.

In this specification, a numerical range indicated by using “to” or “toabout” shows a range including numerical values written before and after“to” or “to about” as a minimum value and a maximum value, respectively.In this specification numerical ranges are used to quantify certainparameters relating to various embodiments. It should be understood thatwhen numerical ranges are provided, such ranges are to be construed asproviding literal support for claim limitations that only recite thelower value of the range as well as claim limitations that only recitethe upper value of the range. For example, a disclosed numerical rangeof “about 10 to about 100” provides literal support for a claim recitinggreater than about 10 (with no upper bounds) and a claim reciting lessthan about 100 (with no lower bounds). Furthermore, in the case of allthe relative or percentage amount information, particularlyweight-related amount information, that this information is to beselected by a person having ordinary skill in the art, within the scopeof the present invention, in such a manner that the sum of therespective ingredients, active ingredients, additives or ancillarysubstances, or the like always come up to 100% or 100% w/w.

With respect to the claims below, if a specific number of an introducedclaim recitation is intended, such an intent will be explicitly recitedin the claim, and in the absence of such recitation no such intent ispresent. For example, as an aid to understanding, the claims in thisspecification may contain usage of the introductory phrases “at leastone” and “one or more” to introduce claim recitations. However, the useof such phrases should not be construed to imply that the introductionof a claim recitation by the indefinite articles “a” or “an” limits anyparticular claim containing such introduced claim recitation toembodiments containing only one such recitation, even when the sameclaim includes the introductory phrases “one or more” or “at least one”and indefinite articles such as “a” or “an” (e.g., “a” and/or “an”should be interpreted to mean “at least one” or “one or more”); the sameholds true for the use of definite articles used to introduce claimrecitations. In addition, even if a specific number of an introducedclaim recitation is explicitly recited, it should be understood thatsuch recitation means at least the recited number (e.g., the barerecitation of “two recitations,” without other modifiers, means at leasttwo recitations, or two or more recitations). In those instances where aconvention analogous to “at least one of A, B, and C, etc.” is used, ingeneral such a construction is intended in the sense one having ordinaryskill in the art would understand the convention (e.g., “a system havingat least one of A, B, and C” would include but not be limited to systemsthat have A alone, B alone, C alone, A and B together, A and C together,B and C together, and/or A, B, and C together, etc.). In those instanceswhere a convention analogous to “at least one of A, B, or C, etc.” isused, in general such a construction is intended in the sense one havingordinary skill in the art would understand the convention (e.g., “asystem having at least one of A, B, or C” would include but not belimited to systems that have A alone, B alone, C alone, A and Btogether, A and C together, B and C together, and/or A, B, and Ctogether, etc.).

In this written description, references to “one embodiment”, “anembodiment”, or “embodiments” mean that the feature or features beingreferred to are included in at least one embodiment of the presentinvention. Separate references to “one embodiment”, “an embodiment”, or“embodiments” in this written description do not necessarily refer tothe same embodiment and are also not mutually exclusive unless so statedand/or except as will be readily apparent to those having ordinary skillin the art from the description. For example, a feature, structure, act,etc. described in one embodiment may also be included in otherembodiments, but is not necessarily included. Thus, the presentinvention encompasses a variety of combinations and/or integrations ofthe specific embodiments described in the specification and any suitablecombination of the previously described embodiments may be made withoutdeparting from the spirit of the present invention.

This disclosure is to be construed as exemplary only and does notdescribe every possible embodiment since describing every possibleembodiment would be impractical. Numerous alternative embodiments may beimplemented, using either current technology or technology developedafter the filing date of this patent application, which would still fallwithin the scope of the present invention.

The inventors hereby state their intent to rely on the Doctrine ofEquivalents to determine and assess the reasonably fair scope of thepresent invention as pertains to any process, machine, manufacture, orcomposition of matter not materially departing from but outside theliteral scope of the invention as set forth in the following claims.

1. (canceled)
 2. A medical device comprising: a squeezable reservoircontaining a pharmaceutical gel formulation; and a site-specificapplicator projecting from the reservoir, said site specific applicatorpresenting a proximal end and a distal end, said site-specificapplicator including a wall defining an inner margin extending betweenthe proximal end and the distal end, said inner margin having a widthranging from 0.5 mm to 2 mm, said inner margin defining an opening atthe distal end, said inner margin being arranged in fluid communicationwith the reservoir such that the sucralfate formulation is expelledtherethrough and out of the opening when the reservoir is squeezed,wherein said pharmaceutical gel formulation has a sucralfateconcentration ranging from 3% w/w to about 15% w/w.
 3. The medicaldevice as claimed in claim 2, said squeezable reservoir being in theshape of a tube.
 4. The medical device as claimed in claim 2, whereinsaid pharmaceutical gel formulation is capable of being stored in saidsqueezable tube for a period of time of 1-year, and wherein saidpharmaceutical gel formulation is capable of being expelled from thesqueezable reservoir through the inner margin throughout the period oftime.
 5. The medical device as claimed in claim 4, said period of timeis 2-years.
 6. The medical device as claimed in claim 2, saidsite-specific applicator having a conical shape.
 7. The medical deviceas claimed in claim 2, said inner margin having a circular shape.
 8. Themedical device as claimed in claim 7, said inner margin presenting adiameter in the range from 0.5 mm to 2 mm.
 9. The medical device asclaimed in claim 2, said width being about the same along the innermargin.
 10. The medical device as claimed in claim 2, wherein saidsite-specific applicator is removably fixed to the reservoir.
 11. Themedical device as claimed in claim 2, further comprising a removableclosure arranged at the distal end of the site-specific applicator. 12.The medical device as claimed in claim 2, said pharmaceutical gelformulation further comprising: malic acid, as an API solubilizer, in aconcentration ranging from about 4.8% w/w to about 5.2% w/w; calciumcarbonate, as a cross-linking agent, in a concentration ranging fromabout 2.4% w/w to about 2.6% w/w; calcium sulfate dihydrate, as aconsistency improver, in a concentration ranging from about 0.05% w/w toabout 1.5% w/w; xanthan gum, as a rheology modifier, in a concentrationranging from about 0.1% w/w to about 1.0% w/w; and propylene glycol, asa humectant, in a concentration ranging from about 2% w/w to about 10%w/w.
 13. The medical device as claimed in claim 2, wherein saidpharmaceutical formulation has a water content ranging from an about 56%w/w to about 85% w/w.
 14. The medical device as claimed in claim 2, saidpharmaceutical gel formulation further comprising sucralose, as asweetener.
 15. The medical device as claimed in claim 2, wherein saidreservoir and said site-specific applicator being formed from acopolymer.
 16. The medical device as claimed in claim 2, said reservoircomprising an inner layer and an outer layer.
 17. The medical device asclaimed in claim 16, said inner layer comprising an aluminum alloy. 18.The medical device as claimed in claim 16, said outer layer comprisingpolyethylene.
 19. The medical device as claimed in claim 16, saidreservoir further comprising a tie-layer arranged between the innerlayer and the outer layer.
 20. The medical device as claimed in claim19, said tie-layer comprising an ethylene acrylic acid copolymer.